CAR and PXR are members of the NR1I subfamily within the nuclear receptor superfamily. My laboratory was the first to characterize CAR as a drug-activated nuclear receptor, leading world-wide investigations to characterize them and establish their biological roles. Both CAR and PXR regulate not only hepatic drug metabolism and disposition but also energy metabolism such as gluconeogenesis and lipogenesis and ketogenesis. In addition, they regulate cell growth and death signals as well, which includes JNK1, p38MAPK, AKT and GADD45 signals. Consequently, CAR and PXR have now been implicated in various hepatic toxicities and diseases. It is now known that these receptors act as transcription factors as well as signal transducers in these regulations. However, their molecular mechanisms are not fully understood now. Our work found that CAR is phosphorylated at threonine 38 within the DBD and is inactivated. This phosphorylation is the underlying principle through which CAR functions diverge.. For example, phenobarbital stimulates dephosphorization of threonine 38 by protein phosphatase 2A, by binding EGF receptor and/or insulin receptor and repressing their down-stream ERK1/2 signal for CAR activation. ER conserves threonine 38 of CAR at serine 216 within its DBD. With a phosphoSer216peptide antibody, it was found that ER is specifically phosphorylated at serine 216 in immune cells such as neutrophils and macrophages in mice. ER KI (Esr1S216A) mice bearing a non-phosphomimetic alanine mutation were generated to investigate the biological roles of this phosphorylation. ER KI mice are fertile but develop obesity. Analysis of brains and microglia (resident macrophages and the only immune cells in the brain) showed that this phosphorylation confers anti-inflammatory and anti-apoptotic capabilities to ER Phosphorylated ER can be a novel target to investigate various diseases such as obesity and inflammation-related neurodegenerative diseases and their mechanisms. ER KI mice can be an excellent animal model for these investigations. Threonine 38 is not only conserved in ER but also in 41 out of the total 46 human nuclear receptors as well as their corresponding mouse counterparts. Upon activation, a given nuclear receptor coordinates with other nuclear receptors elicit its regulatory function. For example, phenobarbital (PB) is the classic drug that induces hepatic drug metabolizing enzymes such as cytochrome P450. A primary target of PB is nuclear receptor CAR, but, at least, two other nuclear receptors ER and RORneed to be properly regulated for this induction to occur. A critical question raised is how CAR communicates with ER and ROR to coordinate this induction. All three nuclear receptors contain this conserved phosphorylation motif, providing us with the hypothesis that this communication may take place through phosphorylation/dephosphorization of this motif and with an excellent experimental system to investigate the molecular mechanism of this communication in response to drug treatments and/or physiological/pathophysiological conditions. There are 40 nuclear receptors which conserve this motif, enabling us to extend the same line of communication study far beyond these three nuclear receptors.